INTRODUCTION:The incidence of breast cancer in young, premenopausal women has increased over time. For women above the age of 40, it is well-established that mastectomy and breast conserving therapy (BCT)-defined as lumpectomy plus radiation- confer similar outcomes in survival, albeit with a higher rate of local recurrence with BCT. The outcomes of mastectomy versus BCT in young women, however, remain unclear. In this study, we evaluate survival and recurrence risk in women under the age of 40 who have undergone mastectomy versus BCT. METHODS:We performed a retrospective review of all women diagnosed with breast cancer at the age of 40 or younger between 1995 and 2020 at Columbia University Irving Medical Center. Overall survival and recurrence-free survival were compared for patients undergoing mastectomy and BCT. Data were obtained from an established tumor registry and chart review; multivariate analysis was performed. RESULTS:There were 414 women (average age 35 y) identified who were diagnosed with breast cancer at the age of 40 or younger. The median follow-up was 74 mo. In our cohort, 46% had a family history of breast cancer, 20% carried a BRCA gene pathogenic variant, 28% were nulliparous, and 12% presented with pregnancy-associated breast cancer. Distribution by subtype was: hormone receptor positive (HR+)/ human epidermal growth factor receptor negative (HER2-) in 59%, HER2+ in 21%, and HR-/HER2-/triple negative breast cancer in 20%. The stage at time of diagnosis was as follows: stage 0 (10%); stage 1 (24%); stage 2 (41%); stage 3 (14%), and stage 4 (11%). Neoadjuvant chemotherapy was administered to 42% of women per the standard of care, and 64% (n = 216) underwent mastectomy and 36% (n = 119) underwent BCT. Adjuvant radiation was administered to 68% of women (100% of BCT patients). The most common type of recurrence was distant metastasis (62%) compared with local and locoregional recurrence (38%). There was no statistically significant difference in 5-y overall survival (P = 0.24) and recurrence-free survival (P = 0.09) between BCT and mastectomy. On multivariate analysis , after controlling for age, stage, tumor subtype, and BRCA status, there was no difference in mortality (β = 0.018, P = 0.66) and recurrence (β = -0.069, P = 0.34) between patients who underwent BCT versus mastectomy at the last follow-up. CONCLUSIONS:In our cohort with 5-y survival data, BCT is a safe option for women aged 40 y and under who are diagnosed with breast cancer. Despite no survival benefit, young women with breast cancer in our cohort underwent mastectomy more often than lumpectomy. Importantly, most recurrences were distant metastases, suggesting that local therapy choice is less relevant to outcome.

IntroductionRecent ILTS guidance supports liver transplantation for patients with very small intrahepatic cholangiocarcinoma. This guidance was informed mainly by North American and European data. The applicability of these guidelines to the region of Australia and New Zealand is unknown.MethodsA retrospective study was performed to measure clinical outcomes of liver transplantation in the ANZ region to ascertain the applicability of this new guidance to this region. Historic patients having undergone LT for known cholangiocarcinoma or incidentally detected cholangiocarcinoma or mixed type hepatocellular-cholangiocarcinomas on explant histology were identified via a national registry. Data was inputted from all transplant units within the ANZ region.ResultsWe found that 64 patients had either knowingly or unknowingly been transplanted for cholangiocarcinoma or mixed type hepatocellular-cholangiocarcinoma in our region.DiscussionOverall survival for patients with very small intrahepatic cholangiocarcinomas was 80%, in line with the current international data. We also report 5-year overall survival for patients with incidentally detected mixed tumours on explant histology was 68%.

BACKGROUND:Ex vivo normothermic machine perfusion (NMP) is an organ preservation technique that enables an extended assessment of graft suitability before liver transplantation (LT). Established monitoring protocols used during NMP vary significantly in their assessment of transplant suitability when applied to the same grafts. Graft-derived cell-free DNA (gdcfDNA) analysis is an emerging tool for monitoring graft health post-transplantation. We investigated the feasibility of monitoring gdcfDNA during NMP for LT in a proof-of-concept, observational study. METHODS:Serial plasma and bile samples were collected during NMP for 10 consecutive grafts, at 15 min post-machine reperfusion and then 2-h intervals. Digital polymerase chain reaction was used to quantify gdcfDNA at each time point. RESULTS:Five grafts were suitable for LT, there were no cases of primary nonfunction or death in the recipients. gdcfDNA was quantified in all bile and plasma samples (n > 100). In plasma, gdcfDNA concentrations climbed post-machine reperfusion until 4.25 h (median 2.25 h = 15.98 × 10 6 copies/mL, 4.25 h = 40.21 × 10 6 copies/mL). gdcfDNA levels then diverged significantly when comparing the viable and non-viable graft groups (6.25 h, median viable: 117.15 × 10 6 copies/mL versus non-viable: 16.72 × 10 6 copies/mL, P  = 0.01). These opposing trends correlated in each graft and in all cases with the viable/non-viable outcome. There was a trend of gradual decline in bile gdcfDNA from viable grafts post-machine reperfusion; discarded grafts showed more variable patterns of release. CONCLUSIONS:gdcfDNA analysis during NMP is a feasible and potential tool to inform viability assessment during NMP for LT. Bile gdcfDNA monitoring offers the prospect of an objective means to assess the degree of biliary injury associated with organ procurement.

BACKGROUND AND AIM:The C-reactive protein to albumin ratio, albumin-bilirubin index and platelet-albumin-bilirubin index have emerged as prognostic scores in hepatocellular carcinoma, although their clinical utility remains unclear, with ongoing investigation in multiple patient populations. This study aims to report survival outcomes and evaluate these indices in a cohort of patients undergoing liver resection for hepatocellular carcinoma in a tertiary Australian centre. METHODS:This retrospective study reviewed data from the Department of Surgery at Austin Health and electronic health records (Cerner corporation). The impact of pre, intra and post-operative parameters on post-operative complications, overall and recurrence free survival were analyzed. RESULTS:163 liver resections were performed in 157 patients between 2007 and 2020. Post-operative complications occurred in 58 patients (35.6%), with pre-operative albumin < 36.5 g/L (3.41(1.41-8.29),p = 0.007) and open liver resection (3.93(1.38-11.21),p = 0.011) demonstrating independent predictive significance. 1,3 and 5-year overall survival was 91.0%, 76.7% and 66.9% respectively, with a median survival time of 92.7 months (81.3-103.9). Hepatocellular carcinoma recurred in 95 patients (58.3%) with a median time to recurrence of 27.8 months (15.6-39.9). 1,3 and 5 year recurrence-free survival rates were 94.0%, 73.7% and 55.1% respectively. Pre-operative C-reactive protein-albumin ratio > 0.034 was significantly associated with reduced overall (4.39(1.19-16.16),p = 0.026) and recurrence-free (2.53(1.21-5.30),p = 0.014) survival. CONCLUSION:C-reactive protein-albumin ratio > 0.034 is a strong predictor of poor prognosis following liver resection for hepatocellular carcinoma. In addition, pre-operative hypoalbuminemia was associated with post-operative complications, and future studies are required to assess the potential benefits of albumin replacement in reducing post-surgical morbidity.

To the Editor: COVID-19 infection clinical outcomes among patients with alopecia areata (AA) on oral Janus kinase (JAK) inhibitors have not previously been reported despite JAK inhibitors increasingly becoming the treatment of choice for AA.1 Adaptive COVID-19 Treatment Trial 2 found that adjunctive JAK inhibitor baricitinib significantly reduced the time to recovery and was associated with less severe adverse events than remdesivir monotherapy. This drove the US Food and Drug Administration to authorize the emergent use of baricitinib in hospitalized patients with COVID-19 requiring oxygen, underscoring the safety of JAK inhibitors during the COVID-19 infection and the unmet need in COVID-19 treatment that was bridged using a JAK inhibitor.

BACKGROUND & AIMS:The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. We aimed to estimate the pooled global NAFLD incidence.METHODS:We performed a systematic review and meta-analysis of cohort studies of adults without NAFLD at baseline to evaluate the global incidence of ultrasound-diagnosed NAFLD.RESULTS:A total of 63 eligible studies (1,201,807 persons) were analyzed. Studies were from Mainland China/Hong Kong (n = 26), South Korea (n = 22), Japan (n = 14), other (n = 2, Sri Lanka, Israel); 63.8% were clinical center studies; median study year 2000 to 2016; 87% were good quality. Among the 1,201,807 persons at risk, 242,568 persons developed NAFLD, with an incidence rate of 4,612.8 (95% CI 3,931.5-5,294.2) per 100,000 person-years and no statistically significant differences by study sample size (p = 0.90) or study setting (p = 0.055). Males had higher incidence vs. females (5,943.8 vs. 3,671.7, p = 0.0013). Both the obese (vs. non-obese) and the overweight/obese groups (vs. normal weight) were about threefold more likely to develop NAFLD (8,669.6 vs. 2,963.9 and 8,416.6 vs. 3,358.2, respectively) (both p <0.0001). Smokers had higher incidence than non-smokers (8,043.2 vs. 4,689.7, p = 0.046). By meta-regression, adjusting for study year, study setting, and study location, study period of 2010 or after and study setting were associated with increased incidence (p = 0.010 and p = 0.055, respectively). By country, China had a higher NAFLD incidence compared to non-China regions (p = 0.012) and Japan a lower incidence compared to non-Japan regions (p = 0.005).CONCLUSIONS:NAFLD incidence is increasing with a current estimate of 4,613 new cases per 100,000 person-years. Males and overweight/obese individuals had significantly higher incidence rates compared to females and those of normal weight. Public health interventions for prevention of NAFLD are needed with a special emphasis on males, overweight/obese individuals, and higher risk regions.IMPACT AND IMPLICATIONS:Non-alcoholic fatty liver disease (NAFLD) affects approximately 30% of people worldwide and appears to be increasing, but data to estimate the incidence rate are limited. In this meta-analytic study of over 1.2 million people, we estimated an incidence rate of NAFLD of 46.13 per 1,000 person-years with significant differences by sex, BMI, geography, and time-period. As treatment options for NAFLD remain limited, prevention of NAFLD should remain the focus of public health strategies. Studies such as these can help policy makers in determining which and whether their interventions are impactful.

Supplementary Figures S1-S2 from The Retinoblastoma Protein Tumor Suppressor Is Important for Appropriate Osteoblast Differentiation and Bone Development

Background Lung cancer is one of the common cancers and the leading cause of death. Tremendous caregiving burden of informal caregivers of lung cancer causes psychological disorders, such as anxiety and depression. Interventions for informal caregivers of patients with lung cancer to improve their psychological health, which ultimately leads to patients’ positive health outcomes, are crucial. A systematic review and meta-analysis was conducted to: 1) evaluate the effect of non-pharmacological interventions on the outcomes of depression and anxiety for lung cancer patients’ informal caregivers; and 2) compare the effects of interventions with differing characteristics (i.e. intervention types, mode of contact, and group versus individual delivery). Methods Four databases were searched to identify relevant studies. Inclusion criteria for the articles were peer-reviewed non-pharmacological intervention studies on depression and anxiety in lung cancer patients’ informal caregivers published between January 2010 and April 2022. Systematic review procedures were followed. Data analysis of related studies was conducted using the Review Manager Version 5.4 software. Intervention effect sizes and studies’ heterogeneity were calculated. Results Eight studies from our search were eligible for inclusion. Regarding total effect for the caregivers’ levels of anxiety and depression, results revealed evidence for significant moderate effects of intervention on anxiety (SMD -0.44; 95% CI, -0.67, -0.21; p = 0.0002) and depression (SMD -0.46; 95% CI, -0.74, -0.18; p = 0.001). Subgroup analyses for both anxiety and depression of informal caregivers revealed moderate to high significant effects for specific intervention types (cognitive behavioral and mindfulness combined with psycho-education interventions), mode of contact (telephone-based interventions), and group versus individual delivery. Conclusion This review provides evidence that cognitive behavioral and mindfulness-based, telephone-based, individual or group-based interventions were effective for informal caregivers of lung cancer patients. Further research is needed to develop the most effective intervention contents and delivery methods across informal caregivers with larger sample size in randomized controlled trials.

Red blood cells circulating through the brain are briefly but closely apposed to the capillary endothelium. We hypothesized that this contact provides a nearly direct pathway for metabolic substrate transfer to neural cells that complements the better characterized plasma to endothelium transfer. While brain function is considered independent of normal fluctuations in blood glucose concentration, this is not borne out by persons with glucose transporter I (GLUT1) deficiency (G1D). In them, encephalopathy is often ameliorated by meal or carbohydrate administration, and this enabled us to test our hypothesis: Since red blood cells contain glucose, and since the red cells of G1D individuals are also deficient in GLUT1, replacing them with normal donor cells via exchange transfusion could augment erythrocyte to neural cell glucose transport via mass action in the setting of unaltered erythrocyte count or plasma glucose abundance. This motivated us to perform red blood cell exchange in 3 G1D persons. There were rapid, favorable and unprecedented changes in cognitive, electroencephalographic and quality-of-life measures. The hypothesized transfer mechanism was further substantiated by in vitro measurement of direct erythrocyte to endothelial cell glucose flux. The results also indicate that the adult intellect is capable of significant enhancement without deliberate practice.      ClinicalTrials.gov registration: NCT04137692 https://clinicaltrials.gov/ct2/show/NCT04137692

Objective:Hepatocellular carcinoma (HCC) is frequently diagnosed late. Although ultrasound-based HCC screening is recommended, its effectiveness is restricted by underutilization. This study aimed to develop a nurse-led decision counseling program used to improve HCC screening in patients with hepatitis B and to evaluate its feasibility in terms of process, resources, management, and cultural acceptance.Methods:The nurse-led decision counseling program was developed following the Medical Research Council framework and the preventive health model. Its components were informed by a systematic review and a qualitative study that had explored empirical HCC screening barriers. Guided by typology of Tickle-Degnen, a feasibility study was conducted among twenty eligible patients with hepatitis B, who were randomized to receive the intervention plus usual care or usual care only. Multisets of feasibility data were collected from interviews, field notes, and minutes of discussions with participants, family members, and clinical specialists.Results:The program consists of health education, tailored information, values clarification exercises, and exploring and addressing barriers, which help to achieve informed and value-based HCC screening utilization. Feasibility assessments identified and improved process issues, such as restrictive inclusion criteria and cultural challenges, including (1) default mistrust, (2) discrimination and confidentiality concerns, (3) cultural reluctance to open discussions about HCC screening, and (4) social influence under a collectivist culture.Conclusions:The study informs an innovative feasibility typology for nursing interventions and contributes to a promising, feasible, and culturally relevant intervention to improve HCC screening and prevent advanced diagnosis in hepatitis B-induced HCC in China and other hepatitis B-prevalent Asian countries.Trial registration:Clinicaltrials.gov: NCT04659005.

Genetic medicines have the potential to treat various diseases; however, certain ailments including inflammatory diseases and cancer would benefit from control over extracellular localization of therapeutic proteins. A critical gap therefore remains the need to develop and incorporate methodologies that allow for posttranslational control over expression dynamics, localization, and stability of nucleic acid–generated protein therapeutics. To address this, we explored how the body’s endogenous machinery controls protein localization through signal peptides (SPs), including how these motifs could be incorporated modularly into therapeutics. SPs serve as a virtual zip code for mRNA transcripts that direct the cell where to send completed proteins within the cell and the body. Utilizing this signaling biology, we incorporated secretory SP sequences upstream of mRNA transcripts coding for reporter, natural, and therapeutic proteins to induce secretion of the proteins into systemic circulation. SP sequences generated secretion of various engineered proteins into the bloodstream following intravenous, intramuscular, and subcutaneous SP mRNA delivery by lipid, polymer, and ionizable phospholipid delivery carriers. SP-engineered etanercept/TNF-α inhibitor proteins demonstrated therapeutic efficacy in an imiquimod-induced psoriasis model by reducing hyperkeratosis and inflammation. An SP-engineered anti-PD-L1 construct mediated mRNA encoded proteins with longer serum half-lives that reduced tumor burden and extended survival in MC38 and B16F10 cancer models. The modular nature of SP platform should enable intracellular and extracellular localization control of various functional proteins for diverse therapeutic applications.

Background: The globally endemic hepatocellular carcinoma induced by hepatitis B highlights the need for an ultrasonography-based screening strategy to reduce the tumour burden. However, patient non-adherence due to unawareness and complex decisions in weighting uncertainties of hepatocellular carcinoma screening has continuously challenged its continuum.Objective: To examine the effectiveness and process of a nurse-led decision counselling programme for improving hepatocellular carcinoma screening among patients with hepatitis B.Design: Single-blind randomised controlled trial.Setting and participants: Between 12 March and 19 July 2021, 178 patients with hepatitis B were recruited from six inpatient wards of a university-affiliated hospital in northern China.Methods: Participants were randomly allocated to receive usual care (n = 89) or usual care plus a nurse-led decision counselling programme (n = 89). Underpinned by the preventive health model, the programme consisted of health education, tailored information, and values clarification exercises to elicit informed and value-based preferences for hepatocellular carcinoma screening. Screening barriers were explored and addressed through procedural problem-solving. Hepatocellular carcinoma screening rate at six months post-baseline was the primary outcome. Secondary outcomes (knowledge, perceptions, and decision conflicts regarding hepatocellular carcinoma screening) were measured at baseline (T0), immediately after the intervention (T1), and the six-month follow-up (T2). A Medical Research Council framework-guided process evaluation was conducted by drawing on data from intervention documentation, WeChat discussions, and interviews with stakeholders (n = 13).Results: With a mean age of 47.32 (8.78) years, participants mostly occupied rural residences (63.5 %). Compared with the control group, the intervention group had significantly higher hepatocellular carcinoma screening rates (75.6 % vs. 42.1 %, p < 0.001) and displayed greater improvements in the scores of hepatocellular carcinoma screening knowledge (beta = 3.643, 95 % confidence interval [CI] = 3.030, 4.255), salience and coherence (beta = 0.410, 95 % CI = 0.234, 0.586), response efficacy (beta = 0.327, 95 % CI = 0.181, 0.473), and perceived susceptibility (beta = 0.214, 95 % CI = 0.040, 0.388) at T1. Improvement in perceived susceptibility was not maintained, whereas a higher decrease of the decision conflict score was found at T2 (beta = -4.156, 95 % CI = -7.851, -0.461). The process evaluation revealed potential intervention mechanisms and contextual factors affecting intervention effectiveness, such as living status and natural disasters.Conclusion: The programme was effective in improving hepatocellular carcinoma screening and showed that nurses could play a decision counselling role in optimising the screening among patients with hepatitis B.

Introduction: In Australia and New Zealand, liver allocation is needs based (based on model for end-stage liver disease score). An alternative allocation system is a transplant benefit-based model. Transplant benefit is quantified by complex waitlist and transplant survival prediction models. Research Questions: To validate the UK transplant benefit score in an Australia and New Zealand population. Design: This study analyzed data on listings and transplants for chronic liver disease between 2009 and 2018, using the Australia and New Zealand Liver and Intestinal Transplant Registry. Excluded were variant syndromes, hepatocellular cancer, urgent listings, pediatric, living donor, and multi-organ listings and transplants. UK transplant benefit waitlist and transplant benefit score were calculated for listings and transplants, respectively. Outcomes were time to waitlist death and time to transplant failure. Calibration and discrimination were assessed with Kaplan–Meier analysis and C-statistics. Results: There were differences in the UK and Australia and New Zealand listing, transplant, and donor populations including older recipient age, higher recipient and donor body mass index, and higher incidence of hepatitis C in the Australia and New Zealand population. Waitlist scores were calculated for 2241 patients and transplant scores were calculated for 1755 patients. The waitlist model C-statistic at 5 years was 0.70 and the transplant model C-statistic was 0.56, with poor calibration of both models. Conclusion: The UK transplant benefit score model performed poorly, suggesting that UK benefit-based allocation would not improve overall outcomes in Australia and New Zealand. Generalizability of survival prediction models was limited by differences in transplant populations and practices.

INTRODUCTION:Approximately 132,000 Afghans have resettled in the United States since the 1980s and are now aging. As older adults, sociocultural factors influence health and health-related behaviors. This study aimed to explore older Afghan refugee women's perceptions of individual and sociocultural factors of health and health care experiences.METHODS:A focused ethnography methodology was conducted with 27 semi-structured interviews with older Afghan refugee women, family members, and community key informants in Southern California. Recorded interviews were transcribed and analyzed using inductive thematic analysis.RESULTS:Five themes were identified as key to health promotion in the post-migration setting: (a) health promotion through Islam, (b) the centrality of family, (c) ongoing stressors that impact health, (d) needing support in navigating health services, and (e) miscommunication leading to mistrust of health care providers.DISCUSSION:Health interventions should consider social and cultural contexts and faith-based and family-centered approaches when addressing older Afghan refugee women's long-term health and well-being.